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(s, OCH3), 3.31–3.40 (m, CH, OCH3, and CH2OCH3),
3.52–3.57 (m, CHCHH0OCH3), 3.62–3.67 (m,
CHCHH0OCH3), 4.42 (d, J ¼ 6:0 Hz, CH2Ph), 7.22–
7.32 (m, 5PhH), 7.96 (br s, NH); 13C NMR (CDCl3)
42.5, 47.6, 58.1, 58.2, 62.1, 71.4, 72.3, 126.7, 127.0,
128.0, 138.0, 171.5 ppm; MS (+CI) (rel intensity) 268
(17), 267 (Mþ+1, 100), 208 (26); Mr (+CI) 267.17120
[Mþ+1] (calcd for C14H23N2O3 267.17087).
method A. Purification was by column chromatography
(SiO2; 1:49, MeOH–CHCl3): mp 85–86 ꢁC; Rf 0.29 (1:49,
MeOH–CHCl3); IR (KBr) 3228, 3042, 2925, 2183, 2044,
1645, 1544, 1242, 1090, 971, 698 cmÀ1
;
1H NMR
(CDCl3) d 3.76 (s, CH), 4.43 (dd, J ¼ 5:8, 14.4 Hz,
CHH0Ph), 4.49 (dd, J ¼ 6:1, 14.4 Hz, CHH0Ph), 7.21–
7.38 (m, 10PhH), the signal for the NH proton was not
detected; 13C NMR (CDCl3) 43.2, 77.0, 127.4, 127.8,
128.0, 128.4, 128.6, 128.7, 136.6, 138.4, 171.6 ppm, the
CD3 signals were not detected; MS (+CI) (rel intensity)
276 (15), 275 (Mþ+1, 100), 140 (24); Mr (+CI) 275.20381
[Mþ+1] (calcd for C17H15D6N2O 275.20305). Anal.
Calcd for C17H14D6N2O: C, 74.61; H, 7.35 (calculated
H+D as H); N, 10.19. Found: C, 74.61; H, 7.41; N,
10.19.
4.22. Synthesis of( R,S)-N-benzyl-2-dimethylamino-3-
methoxypropionamide (29)
Compound 29 (3.15 g, 97%) was prepared as a pale-
yellow oil from 45 (3.75 g, 13.79 mmol) and dimethyl-
amine (2.0 M in THF, 25 mL, 50 mmol) at room tem-
perature (18 h) utilizing method A. Purification was by
column chromatography (SiO2; 1:49, MeOH–CHCl3):
Rf 0.27 (1:49, MeOH–CHCl3); IR (neat) 3322 (br), 1662,
4.25. Synthesis of( R)-N-benzyl-2-ethylamino-3-meth-
oxypropionamide ((R)-26)
1
1523 cmÀ1; H NMR (CDCl3) d 2.35 (s, N(CH3)2), 3.05
(dd, J ¼ 3:6, 5.7 Hz, CH), 3.24 (s, OCH3), 3.71 (dd,
J ¼ 5:7, 10.5 Hz, CHH0OCH3), 3.82 (dd, J ¼ 3:6,
10.5 Hz, CHH0OCH3), 4.43 (dd, J ¼ 5:3, 14.4 Hz,
CHH0Ph), 4.50 (dd, J ¼ 5:3, 14.4 Hz, CHH0Ph), 7.22–
7.35 (m, 5PhH), 7.57 (br s, NH); 13C NMR (CDCl3)
42.8, 43.0, 58.8, 69.6, 70.4, 127.2, 127.5, 128.5, 138.5,
171.4 ppm; MS (+CI) (rel intensity) 238 (17),
237 (Mþ+1, 100), 102 (41); Mr (+CI) 237.15994 [Mþ+1]
(calcd for C13H21N2O2 237.16030). Anal. Calcd for
C13H20N2O2: C, 66.07; H, 8.53; N, 11.86. Found: C,
65.89; H, 8.69; N, 11.81.
To a MeOH (50 mL) solution of (R)-246 (887 mg,
4.24 mmol) and sodium cyanoborohydride (187 mg,
2.97 mmol) was added acetaldehyde (250 lL, 4.45 mmol)
in one portion and then the mixture was stirred at room
temperature (10 min). The reaction solvent was evapo-
rated and the crude was purified by column chroma-
tography (SiO2; 1:49, MeOH–CHCl3) to obtain (R)-26
as a pale-yellow oil (511 mg, 51%): Rf 0.32 (1:49,
MeOH–CHCl3); IR (neat) 3319 (br), 3062, 3033, 1661,
1526 cmÀ1
;
1H NMR (CDCl3) d 1.08 (t, J ¼ 7:2 Hz,
CH2CH3), 1.64 (br s, NH), 2.55–2.71 (m, CH2CH3),
3.31–3.37 (m, CH), 3.36 (s, OCH3), 3.56 (dd, J ¼ 7:2,
9.6 Hz, OCHH0), 3.67 (dd, J ¼ 4:2, 9.6 Hz, OCHH0),
4.47 (d, J ¼ 6:3 Hz, CH2Ph), 7.25–7.36 (m, 5PhH), 7.84
(br s, NH), addition of excess (R)-())-mandelic acid27 to
a CDCl3 solution containing (R)-26 gave only one signal
for the methoxy methyl protons (d 3.06) and the N-ethyl
methyl protons (d 1.02); 13C NMR (CDCl3) 15.3, 42.9,
43.1, 58.7, 62.5, 72.6, 127.2, 127.3, 128.5, 138.3,
172.1 ppm; MS (+CI) (rel intensity) 238 (15), 237
(Mþ+1, 100), 102 (15); Mr (+CI) 237.16032 [Mþ+1]
(calcd for C13H21N2O2 237.16030). Anal. Calcd for
C13H20N2O2Æ0.25H2O: C, 64.84; H, 8.58; N, 11.63.
Found: C, 64.89; H, 8.60; N, 11.59.
4.23. Synthesis of( R,S)-N-benzyl-2-morpholin-4-yl-3-
methoxypropionamide (30)
Compound 30 (950 mg, 80%) was prepared as a clear
thick oil from 45 (1.17 g, 4.30 mmol) and morpholine
(20 mL, 229 mmol) at 45 ꢁC (2 d) utilizing method A.
Purification was by column chromatography (SiO2;
1:49, MeOH–CHCl3): Rf 0.35 (1:49, MeOH–CHCl3); IR
1
(neat) 3319 (br), 1662, 1521 cmÀ1; H NMR (CDCl3) d
2.54–2.73 (m, CH2NCH2), 3.11 (dd, J ¼ 3:5, 5.6 Hz,
CH), 3.32 (s, OCH3), 3.60–3.74 (m, CH2OCH2 and
CHH0OCH3), 3.83 (dd, J ¼ 3:5, 10.4 Hz, CHH0OCH3),
4.42 (dd, J ¼ 6:0, 14.9 Hz, CHH0Ph), 4.50 (dd, J ¼ 6:3,
14.9 Hz, CHH0Ph), 7.24–7.35 (m, 5PhH), 7.63 (br s,
NH); 13C NMR (CDCl3) 42.9, 50.8, 58.7, 66.9, 68.7,
69.6, 127.1, 127.2, 128.4, 138.2, 170.6 ppm; MS (+CI)
(rel intensity) 280 (16), 279 (Mþ+1, 100), 144 (11); Mr
(+CI) 279.17118 [Mþ+1] (calcd for C15H23N2O3
279.17087). Anal. Calcd for C15H22N2O3Æ0.2H2O: C,
63.90; H, 8.01; N, 9.94. Found: C, 63.81; H, 8.06; N,
10.00.
4.26. Synthesis of( R,S)-N-benzyl-2-dimethylamino-2-
phenylacetamide-N-oxide (51)
A CH2Cl2 (3 mL) solution of 19 (50 mg, 0.19 mmol) and
m-chloroperoxybenzoic acid (42 mg, 0.19 mmol) was
stirred at room temperature (2 h). The solvent was
evaporated in vacuo and the residue was purified by
PTLC (SiO2, 1:1, Et2O–MeOH): Rf 0.27 (1:1, Et2O–
1
MeOH); H NMR (CDCl3) d 2.89 (s, NCH3), 3.32 (s,
4.24. Synthesis of( R,S)-N-benzyl-2-dimethyl-d6-amino-2-
phenylacetamide (46)
NCH03), 4.50 (dd, J ¼ 5:9, 15.3 Hz, CHH0Ph), 4.56 (dd,
J ¼ 6:4, 15.3 Hz, CHH0Ph), 4.75 (s, CH), 11.71 (br s,
NH), 7.24–7.43 (m, 8PhH), 7.70 (d, J ¼ 7:5 Hz, 2PhH),
11.71 (br s, NH); 13C NMR (CDCl3) 42.9, 58.0, 59.6,
80.9, 127.1, 127.6, 128.3, 128.6, 130.0, 130.9, 138.1,
166.6 ppm, one aromatic carbon signal was not detected
and is believed to overlap with nearby peaks.
Compound 46 (710 mg, 55%) was prepared as a white
solid from 39 (1.22 g, 4.70 mmol), dimethyl-d6-amine
hydrochloride (5.00 g, 57.08 mmol), Et3N (8.0 mL,
57.08 mmol), and THF (20 mL) at 50 ꢁC (7 d) utilizing